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1.  Exploring polymorphisms in B-DNA helical conformations 
Nucleic Acids Research  2012;40(21):10668-10678.
The traditional mesoscopic paradigm represents DNA as a series of base-pair steps whose energy response to equilibrium perturbations is elastic, with harmonic oscillations (defining local stiffness) around a single equilibrium conformation. In addition, base sequence effects are often analysed as a succession of independent XpY base-pair steps (i.e. a nearest-neighbour (NN) model with only 10 unique cases). Unfortunately, recent massive simulations carried out by the ABC consortium suggest that the real picture of DNA flexibility may be much more complex. The paradigm of DNA flexibility therefore needs to be revisited. In this article, we explore in detail one of the most obvious violations of the elastic NN model of flexibility: the bimodal distributions of some helical parameters. We perform here an in-depth statistical analysis of a very large set of MD trajectories and also of experimental structures, which lead to very solid evidence of bimodality. We then suggest ways to improve mesoscopic models to account for this deviation from the elastic regime.
PMCID: PMC3510489  PMID: 23012264
2.  Arbitrary protein−protein docking targets biologically relevant interfaces 
BMC Biophysics  2012;5:7.
Protein-protein recognition is of fundamental importance in the vast majority of biological processes. However, it has already been demonstrated that it is very hard to distinguish true complexes from false complexes in so-called cross-docking experiments, where binary protein complexes are separated and the isolated proteins are all docked against each other and scored. Does this result, at least in part, reflect a physical reality? False complexes could reflect possible nonspecific or weak associations.
In this paper, we investigate the twilight zone of protein-protein interactions, building on an interesting outcome of cross-docking experiments: false complexes seem to favor residues from the true interaction site, suggesting that randomly chosen partners dock in a non-random fashion on protein surfaces. Here, we carry out arbitrary docking of a non-redundant data set of 198 proteins, with more than 300 randomly chosen "probe" proteins. We investigate the tendency of arbitrary partners to aggregate at localized regions of the protein surfaces, the shape and compositional bias of the generated interfaces, and the potential of this property to predict biologically relevant binding sites. We show that the non-random localization of arbitrary partners after protein-protein docking is a generic feature of protein structures. The interfaces generated in this way are not systematically planar or curved, but tend to be closer than average to the center of the proteins. These results can be used to predict biological interfaces with an AUC value up to 0.69 alone, and 0.72 when used in combination with evolutionary information. An appropriate choice of random partners and number of docking models make this method computationally practical. It is also noted that nonspecific interfaces can point to alternate interaction sites in the case of proteins with multiple interfaces. We illustrate the usefulness of arbitrary docking using PEBP (Phosphatidylethanolamine binding protein), a kinase inhibitor with multiple partners.
An approach using arbitrary docking, and based solely on physical properties, can successfully identify biologically pertinent protein interfaces.
PMCID: PMC3441232  PMID: 22559010
Protein structure; Protein-protein interaction; Docking; Interface prediction
3.  CURVES+ web server for analyzing and visualizing the helical, backbone and groove parameters of nucleic acid structures 
Nucleic Acids Research  2011;39(Web Server issue):W68-W73.
Curves+, a revised version of the Curves software for analyzing the conformation of nucleic acid structures, is now available as a web server. This version, which can be freely accessed at, allows the user to upload a nucleic acid structure file, choose the nucleotides to be analyzed and after optionally setting a number of input variables, view the numerical and graphic results online or download files containing a set of helical, backbone and groove parameters that fully describe the structure. PDB format files are also provided for offline visualization of the helical axis and groove geometry.
PMCID: PMC3125750  PMID: 21558323
4.  A systematic molecular dynamics study of nearest-neighbor effects on base pair and base pair step conformations and fluctuations in B-DNA 
Nucleic Acids Research  2009;38(1):299-313.
It is well recognized that base sequence exerts a significant influence on the properties of DNA and plays a significant role in protein–DNA interactions vital for cellular processes. Understanding and predicting base sequence effects requires an extensive structural and dynamic dataset which is currently unavailable from experiment. A consortium of laboratories was consequently formed to obtain this information using molecular simulations. This article describes results providing information not only on all 10 unique base pair steps, but also on all possible nearest-neighbor effects on these steps. These results are derived from simulations of 50–100 ns on 39 different DNA oligomers in explicit solvent and using a physiological salt concentration. We demonstrate that the simulations are converged in terms of helical and backbone parameters. The results show that nearest-neighbor effects on base pair steps are very significant, implying that dinucleotide models are insufficient for predicting sequence-dependent behavior. Flanking base sequences can notably lead to base pair step parameters in dynamic equilibrium between two conformational sub-states. Although this study only provides limited data on next-nearest-neighbor effects, we suggest that such effects should be analyzed before attempting to predict the sequence-dependent behavior of DNA.
PMCID: PMC2800215  PMID: 19850719
5.  Local and global effects of strong DNA bending induced during molecular dynamics simulations 
Nucleic Acids Research  2009;37(11):3766-3773.
DNA bending plays an important role in many biological processes, but its molecular and energetic details as a function of base sequence remain to be fully understood. Using a recently developed restraint, we have studied the controlled bending of four different B-DNA oligomers using molecular dynamics simulations. Umbrella sampling with the AMBER program and the recent parmbsc0 force field yield free energy curves for bending. Bending 15-base pair oligomers by 90° requires roughly 5 kcal mol−1, while reaching 150° requires of the order of 12 kcal mol−1. Moderate bending occurs mainly through coupled base pair step rolls. Strong bending generally leads to local kinks. The kinks we observe all involve two consecutive base pair steps, with disruption of the central base pair (termed Type II kinks in earlier work). A detailed analysis of each oligomer shows that the free energy of bending only varies quadratically with the bending angle for moderate bending. Beyond this point, in agreement with recent experiments, the variation becomes linear. An harmonic analysis of each base step yields force constants that not only vary with sequence, but also with the degree of bending. Both these observations suggest that DNA is mechanically more complex than simple elastic rod models would imply.
PMCID: PMC2699519  PMID: 19380377
6.  Joint Evolutionary Trees: A Large-Scale Method To Predict Protein Interfaces Based on Sequence Sampling 
PLoS Computational Biology  2009;5(1):e1000267.
The Joint Evolutionary Trees (JET) method detects protein interfaces, the core residues involved in the folding process, and residues susceptible to site-directed mutagenesis and relevant to molecular recognition. The approach, based on the Evolutionary Trace (ET) method, introduces a novel way to treat evolutionary information. Families of homologous sequences are analyzed through a Gibbs-like sampling of distance trees to reduce effects of erroneous multiple alignment and impacts of weakly homologous sequences on distance tree construction. The sampling method makes sequence analysis more sensitive to functional and structural importance of individual residues by avoiding effects of the overrepresentation of highly homologous sequences and improves computational efficiency. A carefully designed clustering method is parametrized on the target structure to detect and extend patches on protein surfaces into predicted interaction sites. Clustering takes into account residues' physical-chemical properties as well as conservation. Large-scale application of JET requires the system to be adjustable for different datasets and to guarantee predictions even if the signal is low. Flexibility was achieved by a careful treatment of the number of retrieved sequences, the amino acid distance between sequences, and the selective thresholds for cluster identification. An iterative version of JET (iJET) that guarantees finding the most likely interface residues is proposed as the appropriate tool for large-scale predictions. Tests are carried out on the Huang database of 62 heterodimer, homodimer, and transient complexes and on 265 interfaces belonging to signal transduction proteins, enzymes, inhibitors, antibodies, antigens, and others. A specific set of proteins chosen for their special functional and structural properties illustrate JET behavior on a large variety of interactions covering proteins, ligands, DNA, and RNA. JET is compared at a large scale to ET and to Consurf, Rate4Site, siteFiNDER|3D, and SCORECONS on specific structures. A significant improvement in performance and computational efficiency is shown.
Author Summary
Information obtained on the structure of macromolecular complexes is important for identifying functionally important partners but also for determining how such interactions will be perturbed by natural or engineered site mutations. Hence, to fully understand or control biological processes we need to predict in the most accurate manner protein interfaces for a protein structure, possibly without knowing its partners. Joint Evolutionary Trees (JET) is a method designed to detect very different types of interactions of a protein with another protein, ligands, DNA, and RNA. It uses a carefully designed sampling method, making sequence analysis more sensitive to the functional and structural importance of individual residues, and a clustering method parametrized on the target structure for the detection of patches on protein surfaces and their extension into predicted interaction sites. JET is a large-scale method, highly accurate and potentially applicable to search for protein partners.
PMCID: PMC2613531  PMID: 19165315
7.  Looking into DNA recognition: zinc finger binding specificity 
Nucleic Acids Research  2004;32(22):6673-6682.
We present a quantitative, theoretical analysis of the recognition mechanisms used by two zinc finger proteins: Zif268, which selectively binds to GC-rich sequences, and a Zif268 mutant, which binds to a TATA box site. This analysis is based on a recently developed method (ADAPT), which allows binding specificity to be analyzed via the calculation of complexation energies for all possible DNA target sequences. The results obtained with the zinc finger proteins show that, although both mainly select their targets using direct, pairwise protein–DNA interactions, they also use sequence-dependent DNA deformation to enhance their selectivity. A new extension of our methodology enables us to determine the quantitative contribution of these two components and also to measure the contributions of individual residues to overall specificity. The results show that indirect recognition is particularly important in the case of the TATA box binding mutant, accounting for 30% of the total selectivity. The residue-by-residue analysis of the protein–DNA interaction energy indicates that the existence of amino acid–base contacts does not necessarily imply sequence selectivity, and that side chains without contacts can nevertheless contribute to defining the protein's target sequence.
PMCID: PMC545445  PMID: 15613596
8.  Base pair opening within B-DNA: free energy pathways for GC and AT pairs from umbrella sampling simulations 
Nucleic Acids Research  2003;31(5):1434-1443.
The conformational pathways and the free energy variations for base opening into the major and minor grooves of a B-DNA duplex are studied using umbrella sampling molecular dynamics simulations. We compare both GC and AT base pair opening within a double-stranded d(GAGAGAGAGAGAG)· d(CTCTCTCTCTCTC) oligomer, and we are also able to study the impact of opening on the conformational and dynamic properties of DNA and on the surrounding solvent. The results indicate a two-stage opening process with an initial coupling of the movements of the bases within the perturbed base pair. Major and minor groove pathways are energetically comparable in the case of the pyrimidine bases, but the major groove pathway is favored for the larger purine bases. Base opening is coupled to changes in specific backbone dihedrals and certain helical distortions, including untwisting and bending, although all these effects are dependent on the particular base involved. Partial opening also leads to well defined water bridging sites, which may play a role in stabilizing the perturbed base pairs.
PMCID: PMC149832  PMID: 12595551
9.  α/γ Transitions in the B-DNA backbone 
Nucleic Acids Research  2002;30(24):5398-5406.
In the crystal structures of protein complexes with B-DNA, α and γ DNA backbone torsion angles often exhibit non-canonical values. It is not known if these alternative backbone conformations are easily accessible in solution and can contribute to the specific recognition of DNA by proteins. We have analysed the coupled transition of the α and γ torsion angles within the central GpC step of a B-DNA dodecamer by computer simulations. Five stable or metastable non-canonical α/γ sub-states are found. The most favourable pathway from the canonical α/γ structure to any unusual form involves a counter-rotation of α and γ, via the trans conformation. However, the corresponding free energy indicates that spontaneous flipping of the torsions is improbable in free B-DNA. This is supported by an analysis of the available high resolution crystallographic structures showing that unusual α/γ states are only encountered in B-DNA complexed to proteins. An analysis of the structural consequences of α/γ transitions shows that the non-canonical backbone geometry influences essentially the roll and twist values and reduces the equilibrium dispersion of structural parameters. Our results support the hypothesis that unusual α/γ backbones arise during protein–DNA complexation, assisting the fine structural adjustments between the two partners and playing a role in the overall complexation free energy.
PMCID: PMC140057  PMID: 12490708
10.  The molecular electrostatic potential and steric accessibility of poly (dI.dC). Comparison with poly (dG.dC) 
Nucleic Acids Research  1981;9(24):7041-7051.
The influence of the amino group of guanine on the molecular electrostatic potential and the accessibility to reactive sites of B-DNA is investigated by comparing the two model double helices poly (dI.dC) and poly (dG.dC). The calculations clarify the “disruptive” role of the guanine amino group on nucleic acid-polypeptide interactions.
PMCID: PMC327660  PMID: 7335499

Results 1-10 (10)